DOCSLIB.ORG

Convergent Use of Phosphatidic Acid for Hepatitis C Virus and SARS-Cov

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Convergent Use of Phosphatidic Acid for Hepatitis C Virus and SARS-Cov bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.443480; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 2 Convergent use of phosphatidic acid for Hepatitis C virus and 3 SARS-CoV-2 replication organelle formation 4 5 Keisuke Tabata1†* , Vibhu Prasad1*, David Paul1‡, Ji-Young Lee1, Minh-Tu Pham1, Woan-Ing 6 Twu1, Christopher J. Neufeldt1, Mirko Cortese1, Berati Cerikan1, Cong Si Tran1, Christian 7 Lüchtenborg2, Philip V’kovski3,4, Katrin Hörmann5, André C. Müller5, Carolin Zitzmann6‼, 8 Uta Haselmann1, Jürgen Beneke7, Lars Kaderali6, Holger Erfle7, Volker Thiel3,4, Volker 9 Lohmann1, Giulio Superti-Furga5,8, Britta Brügger2, and Ralf Bartenschlager1,9,10, & 10 11 Affiliations: 12 1Department of Infectious Diseases, Molecular Virology, Heidelberg University, 13 Heidelberg, Germany 14 2Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany 15 3Institute of Virology and Immunology IVI, Bern, Switzerland. 16 4Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of 17 Bern, Bern, Switzerland. 18 5CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 19 Vienna, Austria. 20 6Institute of Bioinformatics and Center for Functional Genomics of Microbes, University 21 Medicine Greifswald, Greifswald, Germany. 22 7BioQuant, Heidelberg University, Heidelberg, Germany. 23 8Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. 24 9Division Virus-Associated Carcinogenesis, German Cancer Research Center, Heidelberg, 25 Germany 26 10German Center for Infection Research, Heidelberg Partner Site, Heidelberg, Germany 27 28 †Keisuke Tabata: Department of Genetics, Graduate School of Medicine, Osaka University, 29 Osaka, Japan; Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier 30 Biosciences, Osaka University 31 ‡David Paul: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge 32 CB2 0QH, UK 33 ‼Carolin Zitzmann: Los Alamos National Laboratory, Theoretical Biology and Biophysics 34 Los Alamos, NM, USA 35 36 * These authors contributed equally to this work 37 38 & Correspondence: 39 Ralf Bartenschlager: [email protected] ; Phone: +49-6221- 40 564225; Fax: +49-6221-564570 41 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.443480; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 42 Abstract 43 Double membrane vesicles (DMVs) are used as replication organelles by phylogenetically 44 and biologically distant pathogenic RNA viruses such as hepatitis C virus (HCV) and severe 45 acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Viral DMVs are morphologically 46 analogous to DMVs formed during autophagy, and although the proteins required for DMV 47 formation are extensively studied, the lipids driving their biogenesis are largely unknown. 48 Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate 49 acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in viral 50 replication and autophagy. Using DMVs in HCV-replicating cells as model, we found that 51 AGPATs are recruited to and critically contribute to HCV replication and DMV formation. 52 AGPAT1/2 double knockout also impaired SARS-CoV-2 replication and the formation of 53 autophagosome-like structures. By using correlative light and electron microscopy, we 54 observed the relocalization of AGPAT proteins to HCV and SARS-CoV-2 induced DMVs. In 55 addition, an intracellular PA sensor accumulated at viral DMV formation sites, consistent 56 with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from 57 AGPATs, PA is generated by alternative pathways via phosphotidylcholine (PC) and 58 diacylglycerol (DAG). Pharmacological inhibition of these synthesis pathways also impaired 59 HCV and SARS-CoV-2 replication as well as formation of autophagosome-like DMVs. 60 These data identify PA as an important lipid used for replication organelle formation by HCV 61 and SARS-CoV-2, two phylogenetically disparate viruses causing very different diseases, i.e. 62 chronic liver disease and COVID-19, respectively. In addition, our data argue that host- 63 targeting therapy aiming at PA synthesis pathways might be suitable to attenuate replication 64 of these viruses. 65 66 One Sentence Summary 67 Phosphatidic acid is important for the formation of double membrane vesicles, serving as 68 replication organelles of hepatitis C virus and SARS-CoV-2, and offering a possible host- 69 targeting strategy to treat SARS-CoV-2 infection. 70 71 72 Main Text 73 Chronic hepatitis C and COVID-19 are major medical problems. Both diseases are 74 caused by viral infections inflicting a large number of people and having led to millions of 75 deaths 1, 2. Chronic hepatitis C is caused by persistent infection with the hepatitis C virus 76 (HCV), while COVID-19 is due to acute infection with the severe acute respiratory syndrome 77 coronavirus-2 (SARS-CoV-2). Both viruses are biologically very distinct e.g. by having a 78 very narrow tropism and a predominantly persistent course of infection in the case of HCV, 79 contrasting the rather broad tropism and acute self-limiting course of infection in the case of 80 SARS-CoV-2. This biological distinction is reflected by their phylogenetic distance with 81 HCV belonging to the Flaviviridae and SARS-CoV-2 being a member of the Coronaviridae 82 virus family 3. In spite of these differences, both viruses possess a single strand RNA genome 83 of positive polarity that is replicated in membranous vesicles in the cytoplasm of infected 84 cells 4, 5. These vesicles are induced by viral proteins, in concert with cellular factors, and 85 composed of two membrane bilayers, thus corresponding to double-membrane vesicles 86 (DMVs). These DMVs accumulate in infected cells and can be regarded as viral replication 87 organelle. Viral DMVs have morphological similarity to autophagosomes 6, 7, but while 88 autophagy-induced DMVs serve to engulf cellular content and damaged organelles for 89 subsequent degradation, viral DMVs create a conducive and protective environment for 90 productive viral RNA replication. In the case of HCV and SARS-CoV-2, DMVs are derived 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.443480; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 91 from the ER 8, 9, 10 and can be induced by the nonstructural proteins (NS)3, 4A, 4B, 5A and 92 5B in the case of HCV 7 and the viral proteins nsp3-4 in the case of MERS-CoV and SARS- 93 CoV 11, 12, alongside with co-opted host cell proteins and lipids. Here, we set-out to search for 94 common host cell factors exploited by the phylogenetically distant HCV and SARS-CoV-2 to 95 build up their cytoplasmic replication organelle. 96 Using HCV as a model to study DMV biogenesis, we purified DMVs under native 97 conditions and determined their molecular composition by proteomic profiling (Fig. 1A and 98 B). To this end we used human hepatoma cells (Huh7) containing a self-replicating HCV 99 replicon RNA (designated sg4BHA31R; 13) in which NS4B was HA-tagged (fig. S1A). This 100 RNA replicates autonomously and induces an extensive array of DMVs that can be isolated 101 by HA-affinity purification 13. Mass spectrometry-based proteomics analysis identified a total 102 of 1487 proteins significantly enriched in the NS4B-HA sample relative to the untagged 103 technical negative control (using SAINT average P-values >0.95) (data S1). Label free 104 quantitation (LFQ) revealed a major overlap of proteins (1542) between the NS4B-HA 105 complex and HCV-naïve ER membranes purified in parallel from Huh7 cells stably 106 expressing HA-tagged Calnexin (CNX-HA) (Fig. 1B and fig. S1B). Of note, 309 proteins 107 were significantly enriched in the NS4B-HA sample relative to the ER control with an over- 108 representation of proteins involved in RNA metabolism, intracellular vesicle organization and 109 transport as well as endomembrane organization (fig. S2). Given our interest in identifying 110 proteins of relevance for DMV formation, we selected 139 candidates with a bias for proteins 111 involved in vesicle transport and biogenesis as well as lipid metabolism. These candidates 112 were validated with respect to their role in HCV replication by using RNA interference-based 113 screening (Fig. 1C and data S2). In this way we could validate 38 hits as HCV dependency 114 factors. Amongst identified hits were acylglycerolphosphate acyltransferase (AGPAT) 1 and 115 2, two enzymes that catalyze the de novo formation of phosphatidic acid (PA), a precursor to 116 di- and triacylglycerols as well as all glycerophospholipids 14, 15. In addition, PA is involved 117 in signaling and protein recruitment to membranes and, owing to its small and highly charged 118 head group, promotes membrane curvature 16, 17, 18. Since these properties might be involved 119 in DMV formation, we focused our subsequent analysis on AGPATs. 120 AGPATs play crucial roles in lipid homeostasis, because enzyme-inactivating mutations 121 in AGPAT2 are linked to congenital generalized lipodystrophy and defects in PA metabolism 122 as well as autophagy are associated with neurological disorders and chronic obstructive 123 pulmonary disease 18, 19. Moreover, severe lipodystrophy as well as extreme insulin resistance 124 and hepatic steatosis have been observed in AGPAT2-/- mice 14. To date, 11 AGPATs have 125 been identified in mammalian cells. AGPAT1 to 5 preferentially utilize lysophosphatidic acid 126 (LPA) as an acyl donor while AGPAT6 to 11 preferentially utilize alternative 127 lysophospholipid substrates or have a preference for glycerol-3-phosphate.
Load more

Recommended publications
  • Evolution, Dynamic Expression Changes and Regulatory Characteristics of Gene Families Involved in the Glycerophosphate Pathway O
    www.nature.com/scientificreports OPEN Evolution, dynamic expression changes and regulatory characteristics of gene families Received: 2 October 2018 Accepted: 14 August 2019 involved in the glycerophosphate Published: xx xx xxxx pathway of triglyceride synthesis in chicken (Gallus gallus) Liyu Yang1, Ziming Liu1, Kepeng Ou2, Taian Wang1, Zhuanjian Li1,3,4, Yadong Tian1,3,4, Yanbin Wang1,3,4, Xiangtao Kang1,3,4, Hong Li1,3,4 & Xiaojun Liu1,3,4 It is well documented that four gene families, including the glycerophosphate acyltransferases (GPATs), acylglycerophosphate acyltransferases (AGPATs), lipid phosphate phosphohydrolases (LPINs) and diacylglycerol acyltransferases (DGATs), are involved in the glycerophosphate pathway of de novo triglyceride (TG) biosynthesis in mammals. However, no systematic analysis has been conducted to characterize the gene families in poultry. In this study, the sequences of gene family members in the glycerophosphate pathway were obtained by screening the public databases. The phylogenetic tree, gene structures and conserved motifs of the corresponding proteins were evaluated. Dynamic expression changes of the genes at diferent developmental stages were analyzed by qRT-PCR. The regulatory characteristics of the genes were analyzed by in vivo experiments. The results showed that the GPAT, AGPAT and LPIN gene families have 2, 7 and 2 members, respectively, and they were classifed into 2, 4 and 2 cluster respectively based on phylogenetic analysis. All of the genes except AGPAT1 were extensively expressed in various tissues. Estrogen induction upregulated the expression of GPAM and AGPAT2, downregulated the expression of AGPAT3, AGPAT9, LPIN1 and LPIN2, and had no efect on the expression of the other genes. These fndings provide a valuable resource for further investigation of lipid metabolism in liver of chicken.
    [Show full text]
  • Dengue Virus Diverts the Mosquito Phospholipid Metabolism for Replication Thomas Vial
    Dengue virus diverts the mosquito phospholipid metabolism for replication Thomas Vial To cite this version: Thomas Vial. Dengue virus diverts the mosquito phospholipid metabolism for replication. Virology. Université Paul Sabatier - Toulouse III, 2020. English. NNT : 2020TOU30036. tel-02980597 HAL Id: tel-02980597 https://tel.archives-ouvertes.fr/tel-02980597 Submitted on 27 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE En vue de l’obtention du DOCTORAT DE L’UNIVERSITÉ DE TOULOUSE Délivré par l'Université Toulouse 3 - Paul Sabatier Présentée et soutenue par Thomas VIAL Le 29 Juin 2020 Le virus de la dengue détourne le métabolisme des phospholipides du moustique pour sa réplication Ecole doctorale : BSB - Biologie, Santé, Biotechnologies Spécialité : MICROBIOLOGIE Unité de recherche : PHARMA-DEV -Laboratoire Pharmacochimie et Pharmacologie pour le Développement Thèse dirigée par Eric DEHARO Jury M. Louis Lambrechts, Rapporteur M. Jean-Luc Imler, Rapporteur Mme Isabelle Morlais, Examinatrice M. Jean-Charles Portais, Examinateur M. Eric Deharo, Directeur de thèse M. Julien Pompon, Co-directeur de thèse M. Guillaume Marti, Invité Dengue virus diverts the mosquito phospholipid metabolism for effective infection Thomas Vial École Doctorale BSB – Biologie, Santé, Biotechnologies Université Toulouse 3 - Paul Sabatier 2 ACKNOWLEDGMENTS These four years spent on this project have been intense, first by being based in Laos and travelling to Singapore and Toulouse to initiate the project, and then full time in Singapore.
    [Show full text]
  • A Detailed Genome-Wide Reconstruction of Mouse Metabolism Based on Human Recon 1
    UC San Diego UC San Diego Previously Published Works Title A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1 Permalink https://escholarship.org/uc/item/0ck1p05f Journal BMC Systems Biology, 4(1) ISSN 1752-0509 Authors Sigurdsson, Martin I Jamshidi, Neema Steingrimsson, Eirikur et al. Publication Date 2010-10-19 DOI http://dx.doi.org/10.1186/1752-0509-4-140 Supplemental Material https://escholarship.org/uc/item/0ck1p05f#supplemental Peer reviewed eScholarship.org Powered by the California Digital Library University of California Sigurdsson et al. BMC Systems Biology 2010, 4:140 http://www.biomedcentral.com/1752-0509/4/140 RESEARCH ARTICLE Open Access A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1 Martin I Sigurdsson1,2,3, Neema Jamshidi4, Eirikur Steingrimsson1,3, Ines Thiele3,5*, Bernhard Ø Palsson3,4* Abstract Background: Well-curated and validated network reconstructions are extremely valuable tools in systems biology. Detailed metabolic reconstructions of mammals have recently emerged, including human reconstructions. They raise the question if the various successful applications of microbial reconstructions can be replicated in complex organisms. Results: We mapped the published, detailed reconstruction of human metabolism (Recon 1) to other mammals. By searching for genes homologous to Recon 1 genes within mammalian genomes, we were able to create draft metabolic reconstructions of five mammals, including the mouse. Each draft reconstruction was created in compartmentalized and non-compartmentalized version via two different approaches. Using gap-filling algorithms, we were able to produce all cellular components with three out of four versions of the mouse metabolic reconstruction.
    [Show full text]
  • Short Time-Series Expression Transcriptome Data Reveal the Gene Expression Patterns of Dairy Cow Mammary Gland As Milk Yield Decreased Process
    G C A T T A C G G C A T genes Article Short Time-Series Expression Transcriptome Data Reveal the Gene Expression Patterns of Dairy Cow Mammary Gland as Milk Yield Decreased Process Yongliang Fan 1,2, Ziyin Han 1,2, Xubin Lu 1,2 , Abdelaziz Adam Idriss Arbab 1,2, Mudasir Nazar 1,2, Yi Yang 3 and Zhangping Yang 1,2,* 1 College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China; [email protected] (Y.F.); [email protected] (Z.H.); [email protected] (X.L.); [email protected] (A.A.I.A.); [email protected] (M.N.) 2 Joint International Research Laboratory of Agriculture & Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China 3 Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University College of Veterinary Medicine, Yangzhou 225009, China; [email protected] * Correspondence: [email protected]; Tel.: +86-0514-87979269 Abstract: The existing research on dairy cow mammary gland genes is extensive, but there have been few reports about dynamic changes in dairy cow mammary gland genes as milk yield decrease. For the first time, transcriptome analysis based on short time-series expression miner (STEM) and histological observations were performed using the Holstein dairy cow mammary gland to explore gene expression patterns in this process of decrease (at peak, mid-, and late lactation). Histological observations suggested that the number of mammary acinous cells at peak/mid-lactation was Citation: Fan, Y.; Han, Z.; Lu, X.; significantly higher than that at mid-/late lactation, and the lipid droplets area secreted by dairy Arbab, A.A.I.; Nazar, M.; Yang, Y.; cows was almost unaltered across the three stages of lactation (p > 0.05).
    [Show full text]
  • Downloaded Per Proteome Cohort Via the Web- Site Links of Table 1, Also Providing Information on the Deposited Spectral Datasets
    www.nature.com/scientificreports OPEN Assessment of a complete and classifed platelet proteome from genome‑wide transcripts of human platelets and megakaryocytes covering platelet functions Jingnan Huang1,2*, Frauke Swieringa1,2,9, Fiorella A. Solari2,9, Isabella Provenzale1, Luigi Grassi3, Ilaria De Simone1, Constance C. F. M. J. Baaten1,4, Rachel Cavill5, Albert Sickmann2,6,7,9, Mattia Frontini3,8,9 & Johan W. M. Heemskerk1,9* Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome‑wide transcriptomes (57.8 k mRNAs). For 14.8 k protein‑coding transcripts, we assigned the proteins to 21 UniProt‑based classes, based on their preferential intracellular localization and presumed function. This classifed transcriptome‑proteome profle of platelets revealed: (i) Absence of 37.2 k genome‑ wide transcripts. (ii) High quantitative similarity of platelet and megakaryocyte transcriptomes (R = 0.75) for 14.8 k protein‑coding genes, but not for 3.8 k RNA genes or 1.9 k pseudogenes (R = 0.43–0.54), suggesting redistribution of mRNAs upon platelet shedding from megakaryocytes. (iii) Copy numbers of 3.5 k proteins that were restricted in size by the corresponding transcript levels (iv) Near complete coverage of identifed proteins in the relevant transcriptome (log2fpkm > 0.20) except for plasma‑derived secretory proteins, pointing to adhesion and uptake of such proteins. (v) Underrepresentation in the identifed proteome of nuclear‑related, membrane and signaling proteins, as well proteins with low‑level transcripts.
    [Show full text]
  • Congenital Generalized Lipodystrophy
    Lima JG, Dos Santos MCF, de Melo Campos JTA. J Rare Dis Res Treat. (2018) 3(2): 1-6 Journal of www.rarediseasesjournal.com Rare Diseases Research & Treatment Mini-review Open Access Congenital Generalized Lipodystrophy Josivan Gomes Lima1*, Marcel Catão Ferreira dos Santos1, Julliane Tamara Araújo de Melo Campos2 1Departamento de medicina clínica, disciplina de endocrinologia e metabologia. Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN, Brazil. 2Faculty of Health Sciences of Trairi, Federal University of Rio Grande do North (UFRN), Natal, RN, Brazil ABSTRACT Article Info Article Notes Congenital Generalized Lipodystrophy (CGL) is a rare and severe autosomal Received: April 02, 2018 recessive disease. Patients are defective in the storage of body fat and, Accepted: May 11, 2018 consequently, they deposit fat in ectopic tissues, mainly liver, and can develop cirrhosis. Insulin resistance is a typical finding, causing diabetes that require *Correspondence: high daily doses of insulin. In the state of Rio Grande do Norte, Brazil, we Dr. Josivan Gomes Lima, Departamento de medicina clínica, disciplina de endocrinologia e metabologia. Hospital have one of the largest cohorts of patients with CGL. In this article, we review Universitário Onofre Lopes, Universidade Federal do Rio pathophysiology, clinical picture and treatment of this disease. Grande do Norte (UFRN), Natal, RN, Brazil; Email: [email protected] © 2018 Lima JG. This article is distributed under the terms of Introduction the Creative Commons Attribution 4.0 International License. Type 2 diabetes is a world health problem, and usually results Keywords Lipodystrophy from excessive weight and increased visceral fat causing peripheral Berardinelli-Seip syndrome insulin resistance and an inability of the pancreas to release Diabetes insulin to compensate this resistance.
    [Show full text]
  • Messenger RNA Levels of Enzymes Involved in Glycerolipid Synthesis in the Brain of The
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.02.021808; this version posted April 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Messenger RNA levels of enzymes involved in glycerolipid synthesis in the brain of the mouse and its alterations in Agpat2-/- and db/db mice. Lila González-Hódara, Anil K. Agarwalb and Víctor Cortésa,c aDepartment of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, 8331150, Chile. bDivision of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, TX 75390, USA. cContact information: email: [email protected], phone: 56 2 23546389, address: Avenida Libertador Bernardo O´Higgins 340, Santiago, Chile Running title: Glycerolipid enzymes in mouse brain 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.02.021808; this version posted April 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Aims: Expression of genes encoding enzymes involved in glycerolipid and monoacylglycerol pathways in specific brain regions is poorly known and its impact in insulin resistance (IR) and type 2 diabetes (T2D) in the brain remains unreported. We determined mRNA levels of enzymes involved in glycerolipid synthesis in different regions of the mouse brain and evaluated their changes in two models of IR and T2D, the Agpat2-/- and Leprdb/db mice. Methods: Cerebral cortex, hypothalamus, hippocampus and cerebellum were dissected from adult Agpat2-/- mice, Leprdb/db mice and their respective wild type littermates.
    [Show full text]
  • And Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid
    cells Review Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis Roxana Coras 1,2, Jessica D. Murillo-Saich 1 and Monica Guma 1,2,* 1 Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; [email protected] (R.C.); [email protected] (J.D.M.-S.) 2 Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain * Correspondence: [email protected] Received: 22 January 2020; Accepted: 18 March 2020; Published: 30 March 2020 Abstract: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.
    [Show full text]
  • Susceptibility Genes for Lung Diseases in the Major Histocompatibility Complex Revealed by Lung Expression Quantitative Trait Loci Analysis
    ERJ Express. Published on May 12, 2016 as doi: 10.1183/13993003.00114-2016 RESEARCH LETTER | IN PRESS | CORRECTED PROOF Susceptibility genes for lung diseases in the major histocompatibility complex revealed by lung expression quantitative trait loci analysis To the Editor: The major histocompatibility complex (MHC) has been linked with hundreds of diseases [1]. The MHC is one of the most complex regions of the human genome, because of the high gene density, extended linkage disequilibrium (LD) and sequence diversity [2]. Recent genome-wide association studies (GWAS) have identified polymorphisms located in the MHC that are associated with lung diseases and related traits: asthma, cystic fibrosis, idiopathic interstitial pneumonia, lung cancer and lung function. However, due to the limitations of GWAS and tissue-specific characteristics of gene expression [3], the causal genes and genetic mechanisms mediating the heritable risk within this locus remain to be found. The present study has two goals: 1) to identify lung expression quantitative trait loci (eQTL) within the MHC region; and 2) to identify new susceptibility genes for lung diseases/traits by overlaying lung eQTL results and MHC single nucleotide polymorphisms (SNPs) previously associated with lung function and respiratory diseases. Susceptibility alleles for respiratory diseases that function as strong lung eQTL should facilitate the biological interpretation of GWAS results and the identification of causal genes in loci with high gene density and high LD such as the MHC. Study subjects and lung specimens have been described previously [4]. Subjects were from three academic sites: Laval University (Quebec, Canada), University of British-Columbia (Vancouver, Canada) and Groningen University (Groningen, the Netherlands), henceforth referred to as Laval, UBC and Groningen, respectively.
    [Show full text]
  • Transcriptional and Post-Transcriptional Profile of Human Chromosome 21
    Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Methods Transcriptional and post-transcriptional profile of human chromosome 21 Sergey I. Nikolaev,1,5 Samuel Deutsch,1,5 Raphael Genolet,2 Christelle Borel,1 Leila Parand,1 Catherine Ucla,1 Frederic Schu¨tz,3 Genevieve Duriaux Sail,1 Yann Dupre´,1 Pascale Jaquier-Gubler,2 Tanguy Araud,2 Beatrice Conne,1 Patrick Descombes,4 Jean-Dominique Vassalli,1 Joseph Curran,2 and Stylianos E. Antonarakis1,6 1Department of Genetic Medicine and Development, University of Geneva Medical School, CH-1211 Geneva, Switzerland; 2Department of Microbiology and Molecular Medicine, University of Geneva Medical School, CH-1211 Geneva, Switzerland; 3Swiss Bioinformatics Institute, Genopode Builiding, CH-1015 Lausanne, Switzerland; 4Genomics Platform, University of Geneva Medical School, CH-1211 Geneva, Switzerland Recent studies have demonstrated extensive transcriptional activity across the human genome, a substantial fraction of which is not associated with any functional annotation. However, very little is known regarding the post-transcriptional processes that operate within the different classes of RNA molecules. To characterize the post-transcriptional properties of expressed sequences from human chromosome 21 (HSA21), we separated RNA molecules from three cell lines (GM06990, HeLa S3, and SK-N-AS) according to their ribosome content by sucrose gradient fractionation. Poly- ribosomal-associated RNA and total RNA were subsequently hybridized to genomic tiling arrays. We found that ;50% of the transcriptional signals were located outside of annotated exons and were considered as TARs (transcriptionally active regions). Although TARs were observed among polysome-associated RNAs, RT-PCR and RACE experiments revealed that ;40% were likely to represent nonspecific cross-hybridization artifacts.
    [Show full text]
  • Was Gathered from SMR Analysis at the Genome-Wide Significance Level
    Supplementary Table 1: Putative functional genes for AMD from the SMR analysis in CAGE. Detailed information of 16 genes (tagged by 21 probes) was gathered from SMR analysis at the genome-wide significance level. probeID Chr Gene Probe bp topSNP topSNP bp A1 A2 Freq GWAS PGWAS eQTL PeQTL SMR PSMR PHEIDI nsnpHEIDI ILMN_1660436 6 HSPA1A 31797709 rs494620 31838713 A G 0.384 0.079 3.71e-07 0.51 1.4e-74 0.155 9.72e-07 2.64e-08 20 ILMN_1765532 6 RDBP 31919892 rs550513 31920687 T C 0.0979 -0.534 9.46e-91 -0.402 1.82e-16 1.33 2.45e-14 2.48e-07 20 ILMN_1679520 6 AGPAT1 32136453 rs41316748 32019512 C T 0.0403 0.246 7.99e-10 -0.72 1.29e-18 -0.341 4.67e-07 4.8e-06 20 ILMN_2044927 6 RNF5 32148208 rs693906 31835164 C G 0.157 0.153 7.05e-12 0.438 6.09e-27 0.349 7.45e-09 0.000454 20 ILMN_1725170 6 CA425595 32624021 rs9274614 32635846 C G 0.241 -0.141 6.5e-16 1.12 3.51e-267 -0.126 3.5e-15 0.00326 20 ILMN_1721636 7 TSC22D4 100064521 rs7792525 99972122 G A 0.188 0.112 1.09e-08 0.323 2.27e-20 0.347 1.16e-06 0.041 20 ILMN_1688279 7 PVRIG 99818960 rs6953580 99825275 G A 0.216 0.090 1.1e-06 -0.951 1.74e-180 -0.0947 1.56e-06 0.051 20 ILMN_1685534 7 PILRB 99947392 rs7792525 99972122 G A 0.188 0.112 1.09e-08 0.345 1.72e-23 0.325 7.01e-07 0.121 20 ILMN_1723984 7 PILRB 99955692 rs73401450 99981859 C G 0.188 0.112 1.07e-08 1.07 3.28e-205 0.105 1.89e-08 0.183 20 ILMN_1768754 7 PILRB 99965148 rs61735533 99955866 A G 0.188 0.111 1.6e-08 1.19 7.93e-255 0.093 2.48e-08 0.257 20 ILMN_1807712 7 PILRB 99951516 rs1964242 99976703 A G 0.186 0.113 7.07e-09 0.649 4.41e-76 0.175
    [Show full text]
  • Novel Insight Into the Potential Role of AGPAT Gene Family in Triacylglycerols Synthesis in Buffalo
    Novel Insight Into The Potential Role of AGPAT Gene Family in Triacylglycerols Synthesis in Buffalo Xiaoya Ma Guangxi Buffalo research institute Anqin Duan Guangxi buffalo research institute Xingrong Lu Guangxi buffalo research institute Md Mahmodul Hasan Sohel Erciyes University Hamdy Abdel-Shafy Cairo University Ahmed Amin Cairo University Shasha Liang Guangxi buffalo research insititute Tingxian Deng ( [email protected] ) Guangxi Buffalo Research Institute https://orcid.org/0000-0002-7442-6739 Research Keywords: AGPAT1, AGPAT6, buffalo, functional characterization, mammary epithelial cells Posted Date: April 6th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-382481/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/20 Abstract Background: Acylglycerophosphate acyltransferases (AGPATs) are enzymes known to act on the second acylation step in the Kennedy (de novo) pathway to catalyze the conversion of lysophosphatidic acid (LPA) to phosphatidic acid (PA). Although AGPATs have been extensively explored by evolution, expression, and functional studies, little is known about the functional characterization of how many members of the AGPAT family are involved in the triacylglycerols (TAG) synthesis. Therefore, the objective of this study was to characterize the potential functional roles of AGPAT family members in the TAG synthesis and growth of mammary epithelial cells using comparative genomic analysis and RNA interference (RNAi) technology. Results: In the present study, a total of 13 AGPAT genes in buffalo were identied using genome-wide analysis. Among them, 12 AGPAT gene pairs were orthologous between buffalo and cattle. The comparative transcriptomic analysis and real-time quantitative reverse transcription PCR (qRT-PCR) further showed that both AGPAT1 and AGPAT6 were highly expressed in milk samples of buffalo and cattle during lactation.
    [Show full text]